Treatment of basal ganglia-related movement disorders with 2,3-benzodiazepines

ABSTRACT

The present invention relates to compounds, related to 2,3 benzodiazepines, of general formula (I), such as Tofisopam, Girisopam or Nerisopam, for use in the treatment of dyskinesia. The dyskinesia may arise as a side-effect of a therapy for pakinsonism.

The present invention relates to the treatment of basal ganglia-relatedmovement disorders and particularly dyskinesias.

Dyskinesias are abnormal involuntary movement disorders. The abnormalmovements may manifest as chorea (involuntary, rapid, irregular, jerkymovements that may affect the face, arms, legs, or trunk), ballism(involuntary movements similar to chorea but of a more violent andforceful nature), dystonia (sustained muscle contractions, usuallyproducing twisting and repetitive movements or abnormal postures orpositions) or athetosis (repetitive involuntary, slow, sinuous, writhingmovements, which are especially severe in the hands).

Movement and other disorders due to dysfunction of the basal ganglia andrelated brain structures are of major socio-economic importance. Suchdisorders can occur as a consequence of inherited or acquired disease,idiopathic neurodegeneration or they may be iatrogenic. The spectrum ofdisorders is very diverse, ranging from those associated with poverty ofmovement (akinesia, hypokinesia, bradykinesia) and hypertonia (e.g.Parkinson's disease, some forms of dystonia) to the involuntary movementdisorders (hyperkinesias or dyskinesias e.g. Huntington's disease,levodopa-induced dyskinesia, ballism, some forms of dystonia).

Knowledge of the pathophysiological mechanisms that underlie some ofthese disorders makes it likely that similar mechanisms mediatedisorders characterised by either hyperkinesias or dyskinesias. It is tobe expected, therefore, that treatments that are effective in one formof dyskinesia may be beneficial in dyskinesias of different aetiology.

One common way in which dyskinesias arise is as a side-effect ofdopamine replacement therapy for parkinsonism or other basalganglia-related movement disorders. Parkinsonism is a syndrome ofsymptoms characterised by slowness of movement (bradykinesia), rigidityand/or tremor. Parkinsonian symptoms are seen in a variety ofconditions, most commonly in idiopathic parkinsonism (i.e. Parkinson'sdisease) but also following treatment of schizophrenia, exposure totoxins/drugs and head injury. In Parkinson's disease the primarypathology is degeneration of dopaminergic neurons of the substantianigra, pars compacta.

The most widely used symptomatic treatments for parkinsonism usedopamine-replacing agents (e.g. L-DOPA and dopamine receptor agonists).These do, however, have limitations, especially following long-termtreatment. Problems can include a “wearing-off” of the anti-parkinsonianefficacy of the treatment and in particular the appearance of a range ofside-effects. These side-effects may manifest as dyskinesias such aschorea and dystonia. Dyskinesia can be seen either when the patient isundergoing dopamine-replacement therapy (in the case of chorea and/ordystonia) or even when off therapy (when dystonia is prevalent).Ultimately, these side-effects severely limit the usefulness ofdopaminergic treatments.

Another common cause of dyslinesias is the treatment of psychosis withneuroleptic drugs—this is known as tardive dyslinesia.

Dyskinesia also occurs in many other conditions including:

-   -   Huntington's disease    -   idiopathic dystonia    -   Tourette syndrome    -   “off” dystonia in parkinsonism    -   ballism    -   senile chorea

Many attempts have been made to develop agents that will prevent thedevelopment of, and/or treat, dyskinesias although such attempts havemet with limited success. There is, therefore, a need to develop ways bywhich dyskinesias may be treated.

The present invention relates to the treatment of dyskinesias using acompound with the general formula (I)

wherein R is an aryl group, such as phenyl or benzyl, which isoptionally substituted with a C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,hydroxyl, amino, nitro, amido, nitrile or a carboxyl group;

-   -   R¹ is C₁₋₆ alkyl or hydrogen;    -   R² is C₁₋₆ alkoxy, hydrogen, hydroxyl, or halogen; and    -   R³ is C₁₋₆ alkoxy, hydrogen, hydroxyl, or halogen,

Preferably R is selected from one of the following groups:

When R¹ is an alkyl group, it is preferred that R¹ is C₁₋₃ alkyl with C₂alkyl(ethyl) being most preferred.

When R² is an alkoxy group, it is preferred that R² is C₁₋₃ alkoxy withC₁ alkoxy (methoxy) being most preferred.

When R³ is an alkoxy group, it is preferred that R³ is C₁₋₃ alkoxy withC₁ alkoxy (methoxy) being most preferred.

It is preferred that the compound of formula (I) is selected from thegroup of Tofisopam, Girisopam and Nerisopam, which are as follows:

Most preferably the compound of formula (I) is Tofisopam.

It will be appreciated that different stereoisomers of compounds offormula (I) may exist and such stereoisomers may be be employed to treatdyskinesia according to the invention. For instance it will beappreciated that compounds such as Tofisopam have a chiral centre.Accordingly Tofisopam, and other compounds of formula (I) that possess achiral centre, can exist as R and S enantiomers. The present inventionencompasses the use of such compounds as a racemic mixture or the use ofseparated R or S enantiomers.

According to a first aspect of the present invention, there is provideda use of a compound of general formula (I) for the manufacture of amedicament for the treatment of dyskinesia.

According to a second aspect of the present invention, there is provideda composition for use in the treatment of dyskinesia comprising atherapeutically effective amount of a compound of general formula (I)and a pharmaceutically acceptable vehicle.

According to a third aspect of the present invention, there is provideda method for the treatment of dyskinesia comprising administering to aperson or animal in need of said treatment a therapeutically effectiveamount of a compound of general formula (I).

According to a fourth aspect of the present invention, there is provideda use of an agent which modulates the activity of receptors with ligandsof general formula (I) for the manufacture of a medicament for thetreatment of dyskinesia.

By “receptors” we mean receptors located on the cell bodies andterminals of neurons located within the striatum, the internal andexternal segments of the globus pallidus and the substantia nigra in thebrain and thereby induce a neuronal signal which reduces dyskinesia andfor which molecules of general formula (I) act as ligands.

By “dyskinesia” we mean abnormal involuntary movements that areassociated with disorders of brain regions known as the basal ganglia.The dyskinesia may be a “levodopa-induced dyskinesia” that arises as acomplication of the treatment of Parkinson's disease (the most commonbasal ganglia disease). Dyslinesia can physically manifest in two forms,chorea and dystonia. Chorea consists of involuntary, continuous,purposeless, abrupt, rapid, brief, unsustained and irregular movementsthat flow from one part of the body to another. Dystonia refers tosustained muscle contractions that cause twisting and repetitivemovements or abnormal postures.

Dyskinesias may be distinguished from ataxia or catalepsy. Ataxia isusually associated with disorders of a part of the brain called thecerebellum, or its connections. It is characterised by poor motorcoordination. There is a staggering gait (walk) and slurred speech,which may make the person appear “drunk”. Catalepsy is, again, adifferent condition that is impossible to confuse with dyskinesias. Itis usually associated with psychotic disorders. It is characterized byinactivity, decreased responsiveness to stimuli, and a tendency tomaintain an immobile posture. The limbs tend to remain in whateverposition they are placed. Thus, the terms dyskinesia (including choreaand dystonia), ataxia and catalepsy refer to distinct and separatedisorders. They have different physical manifestations and differentcauses.

The present invention is based upon research conducted by the inventorsrelating to the activity of compounds of general formula I. To theirsurprise they found that such compounds have efficacy for reducingdyskinesias. This lead them to realise that several classes of agent maybe used according to the fourth aspect of the invention. These include:

-   -   (i) exogenous 2,3 benzodiazepine receptor ligands;    -   (ii) compounds which enhance synthesis of endogenous 2,3        benzodiazepine receptor ligands;    -   (iii) compounds which enhance release of endogenous 2,3        benzodiazepine receptor ligands;    -   (v) compounds which block the rate of inactivation or metabolism        of endogenous 2,3 benzodiazepine receptor agonists; and    -   (vi) compounds which promote/increase 2,3 benzodiazepine        receptor expression and/or transcription.

The invention is based upon our studies relating to the neuralmechanisms underlying movement disorders. Although we do not wish to bebound by any hypothesis, we believe that movement disorders involveabnormal activity of basal ganglia output pathways and in many casesthis is brought about by abnormal function of striatal efferentpathways. These consist of a “direct” pathway to the medial or internalsegment of the globus pallidus and the pars reticulata of the substantianigra and a “indirect” pathway to the lateral or external segment of theglobus pallidus. One of the pathophysiological hallmarks of dyskinesiais overactivity of the direct striatal output pathway. Conversely, inParkinson's disease the direct striatal output pathway is underactiveand the indirect striatal output pathway is overactive. We believecompounds of general formula (I) bind to receptors located on theterminals of the striatal output neurons that project to the internaland external segments of the globus pallidus and the pars reticulata ofthe substantia nigra and thereby induce a neuronal signal which reducesdyskinesia.

WO 99/06408 and WO 01/04122 disclose molecules that have a core 2, 3benzodiazepine tricyclic structure with superficial similarity to thecompounds of general formula (I). The prior art speculates that suchcompounds may be used in the treatment of a variety of medicalconditions (e.g. Parkinson's disease). However, the compounds usedaccording to the invention are distinguished over this prior art in thatthe rings have different substituents (in particular at R, R² and R³).Furthermore, the compounds of general formula (I) have surprisingutility for treating dyskinesias, that is to say excessive involuntarymovements, and not Parkinson's disease per se, which is characterised bya poverty of movement.

The present inventors conducted experiments with the molecule Tofisopamthat led them to realise that compounds of general formula (1) arehighly effective for the treatment of dyskinesias. For instance, it wasfound that dyskinesias (e.g. chorea and dystonia) do not develop, or areat least reduced, when the compounds are given to subjects ondopamine-replacement therapy for the treatment of a movement disorder.

The compounds (and compositions or medicaments containing them) may beused to treat many types of dyskinesia For instance the compounds may beused to treat dyskinesia associated with Huntington's disease,idiopathic torsion dystonia, tardive dyskinesia or off-dystonia inParkinson's disease and most particularly for dyskinesia associated withmovement disorders such as parkinsonism (e.g. idiopathic Parkinson'sdisease, post-encephalitic parkinsonism or parkinsonism resulting fromhead injury), treatment of schizophrenia, drug intoxication, manganesepoisoning and the like.

The compounds may also be used in the treatment of dyskinesias thatmanifest as hyperkinetic activity (e.g. Tourette's syndrome or attentiondeficit hyperactivity (ADHD)).

The compounds are also useful for treatment of dyskinesias that arise asa side-effect of other therapeutic agents. For instance, the compoundsare useful for the treatment of dyskinesia associated with ropinirole,pramipexole, cabergoline, bromcriptine, lisuride, pergolide, L-DOPA orapomorphine treatment. The compounds are preferably used for thetreatment of dyskinesia associated with L-DOPA or apomorphine treatment.

Levodopa is an aromatic amino acid. The chemical name of levodopa orL-DOPA is (−)-L-α-amino-#-(3,4-dihydroxybenzene)propanoic acid. L-DOPAhas the molecular formula C₉H₁₁NO₄ and a molecular weight of 197.2.Chemically, levodopa is (−)-3-(3,4-dihydroxy-phenyl)-L-alanine. It is acolorless, crystalline compound, slightly soluble in water and insolublein alcohol. L-DOPA has the following structural formula:

Because L-DOPA is an amino acid, it is commonly administered to patientsin combination with carbidopa for the treatment of Parkinson's diseaseand syndrome. The chemical name for carbidopa is(−)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene)propanoic acidmonohydrate. Carbidopa has the empirical formula C₁₀H₁₄N₂O₄.H₂O and amolecular weight of 244.3. Anhydrous carbidopa has a molecular weight of226.3. Sinemet® is a combination of carbidopa and levodopa for thetreatment of Parkinson's disease and syndrome. Sinemet® is described inU.S. Pat. Nos. 4,832,957 and 4,900,755, the contents of which are hereinincorporated by reference. The structural formula of carbidopa is:

In addition, the compounds according to the invention are useful for thetreatment of dyskinesias associated with ropinirole treatment.Ropinirole is a non-ergoline dopamine agonist sold under the trademarkRequip®. Ropinirole is the hydrochloride salt of4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one monohydrochlorideand has an empirical formula of C₁₆H₂₄N₂O.HCl. The molecular weight ofropinirole is 296.84 (260.38 as the free base). Ropinirole is describedin U.S. Pat. Nos. 4,452,808 and 4,824,860, the contents of which arehereby incorporated by reference. The structural formula of ropiniroleis:

The compounds according to the invention are also useful for thetreatment of dyskinesias associated with pramipexole treatment. Thechemical name of pramipexole is(S)-2-amino-4,5,6,7-tetra-hydro-6-(propylamino)benzothiazoledihydrochloride mono-hydrate. Pramipexole dihydrochloride is sold underthe trademark Mirapex®. Pramipexole dihydrochloride has the empiricalformula C₁₀H₁₇N₃S.2HCl.H₂O and a molecular weight of 302.27. Thesynthesis of pramipexole is described in U.S. Pat. Nos. 4,843,086 and4,886,812, the contents of which are herein incorporated by reference.The structural formula of pramipexole dihydrochloride is:

The compounds may also be used for the treatment of dyskinesiasassociated with cabergoline treatment. The chemical name for cabergolineis 1-adamantanamine hydrochloride. It has a molecular weight of 187.71and a molecular formula of C₁₀H₁₈NCl. The structural formula ofcabergoline is:

The compounds may also be used for the treatment of dyskinesiasassociated with bromocriptine treatment. Bromocriptine mesylate is soldunder the trademark Parlodel®. The chemical name for bromocriptinemesylate is Ergotaman-3′,6′,18-trione,2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)-,(5′a)-monomethanesulfonate. The molecular weight of bromocriptinemesylate is 750.70 and it has an empirical formula ofC₃₂H₄₀BrN₅O₅.CH₄SO₃. The structural formula of bromocriptine mesylateis:

The compounds may also be used for the treatment of dyskinesiasassociated with lisuride treatment. The chemical name for lisuride isR(+)-N′-[(8α)-9,10-Didehydro-6-methylergolin-8-yl]-N,N-diethylureahydrogen maleate. Lisuride has a molecular weight of 338.45 and theempirical formula C₂₀H₂₆N₄O. The structural formula of lisuride is:

The compounds may also be used for the treatment of dyskinesiasassociated with pergolide treatment. The chemical name of pergolidemesylate is 8β-[(Methylthio)methyl]-6-propylergolinemonomethanesulfonate. Pergolide mesylate is sold under the trademarkPermax®. Permax has the empirical formula C₁₉H₂₆N₂S.CH₄O₃S and amolecular weight of 410.59. The synthesis of pergolide mesylate isdescribed in U.S. Pat. Nos. 4,797,405 and 5,114,948, the contents ofwhich are herein incorporated by reference. The structural formula ofpergolide mesylate is:

The compounds may also be used for the treatment of dyskinesiasassociated with apomorphine treatment. Apomorphine has the empiricalformula C₁₇H₁₇NO₂ and a molecular weight of 267.33. The structuralformula of apomorphine is:

The compounds are particularly useful for treating dyskinesia caused byagents used to treat movement disorders such as parkinsonism. In thisrespect a preferred use of the compounds is in the treatment ofdyskinetic side-effects associated with L-DOPA, apomorphine or otherdopamine agonist therapy for parkinsonism.

The compounds may be used to treat existing dyslinesias but may also beused when prophylactic treatment is considered medically necessary. Forinstance, when it is considered necessary to initiate L-DOPA therapy andit is feared that dyskinesias may develop.

The compounds may be used to treat dyskinesia as a monotherapy (i.e. useof the compound alone) or they may be used as an adjunct to othertherapeutic agents. For instance, the compounds may be co-administeredwith therapeutic agents to prevent dyslinetic side-effects caused bysuch therapeutic agents (e.g. as an adjunct to L-DOPA or apomorphinegiven to treat parkinsonian patients) or alternatively the compounds maybe given in combination with other treatments which also reducedyskinesia (e.g. μ-opioid receptor antagonists,α₂-adrenoreceptor-antagonists, cannabinoid CB₁-antagonists, NMDAreceptor-antagonists, cholinergic receptor-antagonists, histamineH3-receptor agonists, and globus pallidus/subthalamic nucleuslesion/deep brain stimulation).

In preferred embodiments of the invention the compound of generalformula (1) or agents according to the fourth aspect of the inventionmay be combined with therapeutic agents such as:

-   -   (a) therapeutic agents used in the treatment of parlinsonism,        including Parkinson's disease (e.g. L-DOPA, Chloro-APB,        apomorphine, ropinirole, pramipexole, cabergoline, bromcriptine,        lisuride or pergolide)    -   (b) other therapeutic agents used in the treatment of dyskinesia        (e.g. non selective, δ or μ-opioid receptor antagonists,        α₂-adrenoreceptor-antagonists, cannabinoid CB₁-antagonists,        Histamine H3 agonists, mGLuR antagonists NMDA        receptor-antagonists, Gpi lesion/deep brain stimulation).    -   (c) therapeutic agents used as neuroleptics for the treatment of        schizophrenia, psychosis and the like (e.g. agents with dopamine        receptor antagonist properties, haloperidol clozapine,        fluphenazine and sulpiride).

The compounds may also be used as an adjunct or in combination withknown therapies. For instance, we have found that the combination ofL-DOPA with compounds according to the invention results in movementdisorders such as Parkinson's disease being treated with significantlyreduced dyskinetic side-effects.

The compounds may also be used in combination with a known neurolepticto treat patients suffering from tardive dyskinesia. The termneuroleptic refers to the effects on cognition and behavior ofantipsychotic drugs that reduce confusion, delusions, hallucinations,and psychomotor agitation in patients with psychoses. There is anaturally occurring chemical, a neurotransmitter, in the brain calleddopamine. Dopamine is the chemical messenger in the brain mainlyinvolved with thinking, emotions, behavior and perception. In someillnesses, dopamine may be overactive and upsets the normal balance ofchemicals in the brain. This excess dopamine helps to produce some ofthe symptoms of the illness. The main effect that these drugs have is toblock some dopamine receptors in the brain, reducing the effect ofhaving too much dopamine and correcting the imbalance. This reduces thesymptoms caused by having too much dopamine.

Neuroleptic drugs are a class of antipsychotics. Examples of neurolepticcompounds include: haloperidol (Haldol), chlorpromazine (Thorazine),thioridazine (Mellaril), risperidone (Risperdal), quetiapine (Seroquel),olanzapine (Zyprexa), clozapine (Clozaril), amisulpride (Solian),sertindole (Serdolect), zotepine (Zoleptil), Thiothixene (Navane),Molidone (Moban), Loxapine (Loxitane), Prochlorperazine (Compazine),Trifluoperazine (Stelazine), Perphenazine (Trilafon), and Metaclopramide(Reglan).

Haloperidol has a molecular formula of C₂₁H₂₃ClFNO₂ and a molecularweight of 375.8696 g/mol. Haloperidol is also referred to as Haldol;4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4′-fluorobutyrophenone;gamma-(4-(para-Chlorophenyl)-4-hydroxypiperidino)-para′-fluorobutyrophenone;and Serenace.

Chlorpromazine hydrochloride, a phenothiazine derivative, has a chemicalformula of 2-chloro-10-[3(-dimethylamino)propyl]phenothiazinemonohydrochloride. Chlorpromazine hydrochloride has the molecularformula: C₁₇H₁₉ClN₂S.HCl and a molecular weight of 355.33.

SEROQUEL® (quetiapine fumarate) is an antipsychotic drug belonging to anew chemical class, the dibenzothiazepine derivatives. The chemicaldesignation of quetiapine fumarate is2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanolfumarate (2:1) (salt). Quetiapine fumarate is present in tablets as thefumarate salt. All doses and tablet strengths are expressed asmilligrams of base, not as fumarate salt. Quetiapine fumarate has amolecular formula of C₄₂H₅₀N₆O₄S₂.C₄H₄O₄ and a molecular weight of883.11 (fumarate salt).

The chemical name for clozapine is8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e][1,4]diazepine.Clozapine is a an atypical antipsychotic drug which is a tricyclicdibenzodiazepine derivative. Clozapine is sold under the trademark“CLOZARIL®”. Clozapine has a molecular weight of 326.83 and a molecularformula of C₁₈H₁₉ClN₄.

The chemical name of trifluoperazine hydrochloride is10-[3-(4-methyl-1-piperazinyl) propyl]-2-(trifluoromethyl)phenothiazinedihydrochloride. Trifluoperazine has a molecular weight of 480.43 and amolecular formula of C₂₁H₂₄F₃N₃S.2HCl.

Metoclopramide hydrochloride is a white crystalline, odorless substance,freely soluble in water. The chemical name of metoclopramide is4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxy benzamidemonohydrochloride monohydrate. Metoclopramide has a molecular weight of354.3.

Fluphenazine hydrochloride is a trifluoro-methyl phenothiazinederivative intended for the management of schizophrenia The chemicalname of fluphenazine is4-[3-[2-(Trifluoro-methyl)phenothiazin-10-yl]propyl]-1-piperazineethanoldihydrochloride. The molecular formular of fluphenazine isC₂₂H₂₆F₃N₃OS.2HCl and its molecular weight is 510.44.

Compositions according to the first, second, third or fourth aspects ofthe invention may take a number of different forms depending, inparticular on the manner in which the composition is to be used. Thus,for example, the composition may be in the form of a powder, tablet,capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray,micelle, transdermal patch, liposome or any other suitable form that maybe administered to a person or animal. It will be appreciated that thevehicle of the composition of the invention should be one which is welltolerated by the subject to whom it is given and enables delivery of thecompounds to the brain.

The composition of the invention may be used in a number of ways. Forinstance, systemic administration may be required in which case thecompound may be contained within a composition which may, for example,be ingested orally in the form of a tablet, capsule or liquid.Alternatively, the composition may be administered by injection into theblood stream. Injections may be intravenous (bolus or infusion) orsubcutaneous (bolus or infusion). The compounds may also be administeredby inhalation (e.g. intranasally).

Compounds as defined by general formula (I) may also be administeredcentrally by means of intracerebral, intracerebroventricular, orintrathecal delivery.

The compositions are particularly useful when incorporated into patchesthat may be applied to the skin for transdermal delivery of thecompounds according to general formula (I).

The compound may also be incorporated within a slow or delayed releasedevice. Such devices may, for example, be inserted on or under the skinand the compound may be released over weeks or even months. Such adevice may be particularly useful for patients with long-term dyskinesiasuch as patients on continuous L-DOPA therapy for the treatment ofParkinsonism. The devices may be particularly advantageous when acompound is used which would normally require frequent administration(e.g. at least daily ingestion of a tablet or daily injection).

It will be appreciated that the amount of a compound required isdetermined by biological activity and bioavailability which in turndepends on the mode of administration, the physicochemical properties ofthe compound employed and whether the compound is being used as amonotherapy or in a combined therapy. The frequency of administrationwill also be influenced by the abovementioned factors and particularlythe half-life of the compound within the subject being treated.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

Known procedures, such as those conventionally employed by thepharmaceutical industry (e.g. in vivo experimentation, clinical trialsetc), may be used to establish specific formulations of compositions andprecise therapeutic regimes (such as daily doses of the compounds andthe frequency of administration).

Generally, a daily dose of between 0.01 μg/kg of body weight and 1.0g/kg of body weight of a compound of general formula (I) may be used forthe treatment of dyskinesia depending upon which specific compound isused, more preferably, the daily dose is between 0.01 mg/kg of bodyweight and 100 mg/kg of body weight.

Purely by way of example a suitable dose of tofisopam for treatingL-DOPA induced dyskinesia in subjects with Parkinson's disease isbetween 0.1 mg/kg/day and 100 mg/kg/day (depending upon the healthstatus of the individual). It is preferred that between 0.25 mg/kg/dayand 20 mg/kg/day of tofisopam is given to a person daily and is mostpreferred that about 10 mg/kg/day or 15 mg/kg/day tofisopam is given fortreating dyskinesia induced by L-DOPA.

It will be appreciated that the required dose will be influenced by theroute of administration. When tofisopam is given intravenously 0.1-10mg/kg is a preferred dose whereas higher doses (e.g. 5-15 mg/kg) may bea suitable dose orally.

By way of further example suitable doses of Girisopam or Nerisopam arepreferably 0.5-30 mg/kg.

Daily doses may be given as a single administration (e.g. a daily tabletfor oral consumption or as a single daily injection). Alternatively thecompound used may require administration twice or more times during aday. As an example, tofisopam for treating L-DOPA induced dyskinesia inpatients with Parkinson's disease may be administered as two (or moredepending upon the severity of the dyskinesia) daily doses of between 25mg and 5000 mg in tablet form. A patient receiving treatment may take afirst dose upon waling and then a second dose in the evening (if on atwo dose regime) or at 3 or 4 hourly intervals thereafter. Alternativelya slow release device may be used to provide optimal doses to a patientwithout the need to administer repeated doses.

This invention further provides a pharmaceutical composition comprisinga therapeutically effective amount of the compound of the invention anda pharmaceutically acceptable vehicle. In one embodiment, the amount ofthe compound (e.g. tofisopam) is an amount from about 0.01 mg to about800 mg. In another embodiment, the amount is from about 0.01 mg to about500 mg. When the compound is tofisopam, the amount of tofisopam may bean amount from about 0.01 mg to about 250 mg; preferably about 0.1 mg toabout 60 mg; and more preferably about 1 mg to about 20 mg.

In a further embodiment, the vehicle is a liquid and the composition isa solution. In another embodiment, the vehicle is a solid and thecomposition is a tablet. In a further embodiment, the vehicle is a geland the composition is a suppository.

This invention provides a pharmaceutical composition made by combining atherapeutically effective amount of a compound of general formula I anda pharmaceutically acceptable vehicle.

Compounds of general formula I are preferably combined with apharmaceutically acceptable vehicle prior to administration.

This invention provides a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount of acompound of general formula I and a pharmaceutically acceptable vehicle.

In the subject invention a “therapeutically effective amount” is anyamount of a compound or composition which, when administered to asubject suffering from a disease against which the compounds areeffective, causes reduction, remission, or regression of the disease. A“subject” is a vertebrate, mammal, domestic animal or human being.

In the practice of this invention the “pharmaceutically acceptablevehicle” is any physiological vehicle known to those of ordinary skillin the art useful in formulating pharmaceutical compositions.

In one embodiment, the pharmaceutical vehicle may be a liquid and thepharmaceutical composition would be in the form of a solution. Inanother embodiment, the pharmaceutically acceptable vehicle is a solidand the composition is in the form of a powder or tablet. In a furtherembodiment, the pharmaceutical vehicle is a gel and the composition isin the form of a suppository or cream. In a further embodiment thecompound or composition may be formulated as a part of apharmaceutically acceptable transdermal patch.

A solid vehicle can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the vehicle is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with avehicle having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid vehicles include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid vehicles are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidvehicle such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid vehicle can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid vehicles fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the vehicle can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid vehicles are useful insterile liquid form compositions for parenteral administration. Theliquid vehicle for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Vehicles are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings.

The compounds of general formula I can be administered orally in theform of a sterile solution or suspension containing other solutes orsuspending agents (for example, enough saline or glucose to make thesolution isotonic), bile salts, acacia, gelatin, sorbitan monoleate,polysorbate 80 (oleate esters of sorbitol and its anhydridescopolymerized with ethylene oxide) and the like.

A compound of general formula I can also be administered orally eitherin liquid or solid composition form. Compositions suitable for oraladministration include solid forms, such as pills, capsules, granules,tablets, and powders, and liquid forms, such as solutions, syrups,elixirs, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions, and suspensions.

The compounds may be combined with a pharmaceutically acceptable vehicleand another therapeutically active agent prior to administration. Theother therapeutically active agent may be for the treatment ofparkinsonism (including Parkinson's disease).

In another embodiment of the present invention, the compound maycombined with a pharmaceutically acceptable vehicle and anothertherapeutically active agent, wherein such agent is an antipsychoticagent used for the treatment of psychoses, prior to administration.

An embodiment of the present invention will now be described, by way ofexample, with reference to the accompanying drawings, in which;

FIG. 1 is a graph illustrating the effect of Tofisopam on motor activityinduced by L-DOPA in parkinsonian (MPTP-lesioned) marmosets in Example1;

FIG. 2 is a bar chart illustrating the dose/response relationship of theeffect of Tofisopam on motor activity induced by L-DOPA, cumulated overa 4 hour observation period, in parkinsonian (MPTP-lesioned) marmosetsof Example 1;

FIG. 3 is a series of bar charts (A-D) illustrating the dose/responserelationship of the effect of Tofisopam on activity induced by L-DOPA,broken down into 1 hour time bins, in parkinsonian (MPTP-lesioned)marmosets of Example 1;

FIG. 4 is a graph illustrating the effect of tofisopam (10-20 mg/kg) onL-DOPA induced dyskinesia (A) and parkinsonian disability (B) inparkinsonian (MPTP-lesioned) marmosets of Example 1; and

FIG. 5 is a graph illustrating the effect of tofisopam (5-20 mg/kg) onIL-DOPA induced dyskinesia (A) and parkinsonian disability (B) inparkinsonian (MPTP-lesioned) marmosets of Example 1.

For all figures: *indicates P<0.05; **indicates P<0.01; and ***indicatesP<0.001 compared to L-DOPA+vehicle; non-parametric one-way repeatedmeasures ANOVA (Friedman test) followed by Dunn's multiple comparisontest.

EXAMPLE 1

The effect of Tofisopam on L-DOPA-induced dyskinesia was assessed in theMPTP-lesioned marmoset model of Parkinson's disease.

1.1. Methods

1.1.1 Preparation of MPTP-lesioned marmoset model of Parkinson's diseaseMarmosets (Callithrix jacchus) (bred in a closed colony at theUniversity of Manchester) were rendered parkinsonian by subcutaneousinjection of 2 mg kgl MPTP for 5 consecutive days. The marmosets wereallowed to recover for a minimum of 10 weeks until their parkinsonismbecame stable. The degree of activity and disability before and afterMPTP treatment was assessed using a combination of scales as describedin section 1.1.2. Animals were then treated with L-DOPA for at least 3weeks to prime them to elicit dyskinesia.

1.1.2 Assessment of Behaviour

Behaviour was Assessed using the Following Scales:

(a) Activity—a measure of the motor activity of the animals that isassessed by passive infra-red sensors every five minutes. This measureassesses all movements of the animal including dyskinesia.

(b) Parkinsonian disability—non-parametric measures based on thefollowing scales:

Mobility score: 0=no movement, 1=movement of head on the floor of thecage, 2=movement of limbs, but no locomotion, on the floor of the cage,3=movement of head or trunk on wall of cage or perch, 4=movement oflimbs, but no locomotion, on wall of cage or perch, 5=walking aroundfloor of cage or eating from hopper on floor, 6=hopping on floor ofcage, 7=climbing onto wall of cage or perch, 8=climbing up and down thewalls of the cage or along perch, 9=running, jumping, climbing betweencage walls/perch/roof, uses limbs through a wide range of motion andactivity.

(c) Dyskinesia—non-parametric measures based on the following scale:

Dyskinesia score: 0=Absent, 1=Mild, fleeting, 2=Moderate, notinterfering with normal activity, 3=Marked, at times interfering withnormal activity, 4=Severe, continuous, replacing normal activity.

The behavioural tests were assessed every 30 minutes for 4 hours, bypost hoc analysis of video-recordings by an observer blinded to thetreatment.

1.1.3 Treatments

Marmosets received all treatments as described in Table 1. Thetreatments were randomised such that on each day all marmosets receivedone of the treatments. There was at least 48 hours washout betweentreatments. TABLE 1 Treatment Route of Number Treatment administration 1vehicle oral 2 L-DOPA (15-17.5 mg/kg) oral 3 L-DOPA (15-17.5 mg/kg) +oral Tofisopam (5 mg/kg) 4 L-DOPA (15-17.5 mg/kg) + oral Tofisopam (10mg/kg) 5 L-DOPA (15-17.5 mg/kg) + oral Tofisopam (15 mg/kg) 6 L-DOPA(15-17.5 mg/kg) + oral Tofisopam (20 mg/kg)1.2. Results

FIGS. 1, 2 and 3 illustrate the effect of Tofisopam treatment onL-DOPA-induced motor counts in the MPTP-lesioned marmoset model ofParkinson's disease (see method 1.1.2a).

FIGS. 4 and 5 illustrate the results of two experiments. The figuresdemonstrate that Tofisopam (5-20 mg/kg) reduces the severity ofL-DOPA-induced dyskinesia (see method 1.1.2c) without affecting theantiparkinsonian action (see method 1.1.2b) of L-DOPA.

These data demonstrate that compound as defined by general formula (1)cause a dose-dependent reduction in the severity of L-DOPA-induceddyskinesia. FIGS. 4 and 5, in particular, illustrate that the compoundshave the benefit of reducing dyskinesia without adversely affecting theantiparkinsonian action of L-DOPA. Accordingly compounds according tothe invention are particularly useful for modulating dyskinesia and,unlike prior art benzodiazepine compounds, which have been suggested tobe useful for treating parkinsonism per se.

The MPTP-lesioned primate is the ‘gold standard’ preclinical model ofParkinson's disease. Therefore, these data are highly predictive of abeneficial therapeutic effect of the compounds in the treatment ofL-DOPA-induced dyskinesia in Parkinson's disease patients and otherdyskinesias.

1-25. (canceled)
 26. A method of treating dyskinesia in a subjectcomprising administering to the subject a therapeutically effectiveamount of a compound of the formula (I):

wherein R is an aryl group selected from phenyl or benzyl, which isoptionally substituted with a C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen,hydroxyl, amino, nitro, amido, nitrile or a carboxyl group; R¹ is C₁₋₆alkyl or hydrogen; R² is C₁₋₆ alkoxy, hydrogen, hydroxyl, or halogen;and R³ is C¹⁻⁶ alkoxy, hydrogen, hydroxyl, or halogen.
 27. The method ofclaim 26, wherein R is selected from the following groups:


28. The method of claim 26, wherein when R¹ is an alkyl group it is C₂alkyl(ethyl).
 29. The method of claim 26, wherein when R² is an alkoxygroup, it is C₁ alkoxy (methoxy).
 30. The method of claim 26, whereinwhen R³ is an alkoxy group, it is C₁ alkoxy (methoxy).
 31. The method ofclaim 26, wherein the compound of formula I is selected from the groupcomprising Tofisopam, Girisopam and Nerisoparn as shown below:


32. The method of claim 31, wherein the compound of formula I isTofisopam.
 33. The method of claim 26, wherein the compound is used forthe treatment of dyskinesia associated with movement disorders.
 34. Themethod of claim 33, wherein the compound is used for the treatment ofdyskinesia associated with parkinsonism.
 35. The method of claim 34,wherein the parkinsonism is idiopathic Parkinson's disease orpost-encephalitic parkinsonism.
 36. The method of claim 34, wherein theparkinsonism results from head injury, the treatment of schizophrenia,drag intoxication or manganese poisoning.
 37. The method of claim 26,wherein the compound is used for the treatment of dyskinesia associatedwith Huntington's disease, idiopathic torsion dystonia, or offdystoniain Parkinson's disease.
 38. The method of claim 26, wherein the compoundis used for the treatment of hyperkinetic disorder associated withTourette's syndrome and ADHD.
 39. The method of claim 26, wherein thecompound is used for the treatment of dyskinesia which arises as aside-effect of a therapeutic agent.
 40. The method of claim 39, whereinthe compound is used for the treatment of dyskinesia associated withagents used to treat movement disorders.
 41. The method of claim 39,wherein the agent is used to treat parkinsonism.
 42. SEW) The method ofclaim 41, wherein the agent is a dopamine precursor.
 43. SEW) The methodof claim 41, wherein the agent is a dopamine receptor agonist.
 44. Themethod of claim 41, wherein the agent in L-DOPA.
 45. The method of claim41, wherein the agent is one of Chloro-APB, apomorphine, ropinirole,pramipexole, cabergoline, bromcriptine, lisuride or pergolide.
 46. Themethod of claim 39, wherein the agent is used to treat schizophrenia.47. The method of claim 46, wherein the agent is a neuroleptic.
 48. Themethod of claim 46, wherein the agent has doparaine receptor antagonistproperties.
 49. The method of claim 46, wherein the agent is haloperidolclozapine, fluphenazine or sulpiride.
 50. The method of claim 26,wherein the compound is used for prophylactic treatment.